Abstract 3609: Heart Failure Causes Alterations in the Metabolism of Skeletal Muscle Intermyofibrillar Mitochondria
Alteration in energy metabolism may be the common mechanism in the pathogenesis of both myocardium and skeletal muscle dysfunction in heart failure (HF). Myocardium and skeletal muscle switch between glucose and fat as sources of ATP in physiological and pathological conditions. Similar alterations in selection and oxidation of substrates were described in cardiac and skeletal muscle in HF. We hypothesized that HF causes alterations in bioenergetics in populations of mitochondria from skeletal muscle, and they contribute to the development of peripheral myopathy. Subsarcolemmal (SSM) and intermyofibrillar (IFM) mitochondria were isolated from gastrocnemius muscle of control dogs (N=5) and dogs with pacing-induced HF (N=6). HF was evident by an increase in end diastolic volume (58±6 to 112±25 mL) and a decrease in fractional shortening (32±2% to 16±2%). The approach to mitochondrial function was based on
the measurement of integrated mitochondrial respiratory function (oxidative phosphorylation),
the measurement of the activity of the mitochondrial electron transport chain (ETC) enzymes
the measurement of the maximal activity and kinetic properties of the carnitine palmitoyl transferase I, the rate-limiting step in the fatty acid oxidation pathway.
Skeletal muscle mitochondria isolated from HF dogs have significantly (p<.05) decreased oxidation of substrates that donate electrons to complexes I, II and III. Despite their significantly lower phosphorylation rates (p<.05), IFM from HF achieved maximal respiratory rates upon the collapsing of mitochondrial potential with an uncoupler. The defect in oxidative phosphorylation with normal activities of the individual ETC complexes suggests that mitochondrial phosphor-ylation process (adenine nucleotide translocase, phosphate transporter, or ATP synthase) rather than substrate oxidation is damaged with HF. IFM from HF dogs displayed significantly increased maximal activity of CPT I (20.3±1 to 29.8±4 nmol/min/mg, p=.016) with no change in malonyl CoA sensitivity. In conclusion, moderate severity pacing induced heart failure in dogs is associated with an increased potential to oxidize fatty acids and a defect in the phosphorylation process localized in the IFM of the skeletal muscle.